https://science.sciencemag.org/content/367/6481/eaaw8429
New from this month. Make a note of that scfa.
Updating this. This is an easier summary.
Maternal microbial molecules affect offspring health
https://science.sciencemag.org/content/367/6481/978.full
The early-life period is a critical time: Events that affect fetal development can have lifelong implications. Subtle disturbances during human fetal development affect not only major developmental outcomes, but also phenotypes that may not manifest for decades, such as risk of cardiometabolic disease ( 1 ). Despite this, pregnancy remains a poorly understood physiologic state, and there is relatively little mechanistic knowledge of how the maternal environment affects future disease risk. Studies suggest that maternal microbiota influence cardiometabolic disease risk in offspring; however, the mechanisms underlying this relationship are elusive. On page 1002 of this issue, Kimura et al. ( 2 ) find that, in mice, maternal diet and consequent gut microbiota–derived propionate protects against future obesity and metabolic dysregulation in offspring.
Microbiota, the commensal organisms residing in a particular host location, are underexplored modulators of health and disease. Microbiota in the gut, at the interface of human dietary and systemic metabolism, may have particular relevance for obesity and cardiometabolic disease. However, despite intense interest, there remains a knowledge gap between the myriad of hypothesized functions attributable to gut microbiota and those that have actually been demonstrated through mechanistic interrogation. Key functions of gut microbiota include digestion of diet-derived nutrients, which contain components that are not digestible by the host such as complex polysaccharides and fibers. This microbial action generates short-chain fatty acids (SCFAs), which translocate into the bloodstream and enter host metabolism. SCFAs, including propionate, acetate, and butyrate, can be used as a source of fuel by the host, but also function as active signaling molecules ( 3 ). SCFAs have thus been implicated as key metabolites linking the microbiota to host metabolic outcomes, including obesity and insulin sensitivity ( 4 ), and are generally considered to be protective from metabolic diseases, although data are conflicting ( 5 ).
Microbial protection from metabolic disease
Digestion of fiber by microbiota generates short-chain fatty acids (SCFAs). In pregnant mice, SCFAs, particularly propionate, regulate embryonic development through G protein–coupled receptor 41 (GPR41) and GPR43. This protects offspring from metabolic disease in adulthood.
GRAPHIC: V. ALTOUNIAN/ SCIENCE
The mechanisms linking maternal metabolic status during pregnancy to cardiometabolic disease risk in offspring remain elusive. Maternal microbiota are an emerging target of investigation, potentially modulating both maternal health and fetal development. Despite speculation that transfer of microbes from mother to infant may occur in utero, it is generally accepted that microbial colonization does not occur in a meaningful way until birth, when, depending on the method of birth, maternal vaginal or skin microbes colonize the infant gut ( 6 ). Thus, the maternal microbiota likely influence fetal development in utero through intermediates.
Kimura et al. probed the role of microbial SCFA production on fetal development and outcomes in mouse models. Mice whose mothers were housed in a germ-free facility, and consequently did not have gut microbiota during pregnancy, were highly susceptible to high-fat diet–induced obesity later in life. Further, these offspring displayed evidence of glucose intolerance and insulin resistance, suggesting cardiometabolic disease. The absence of maternal microbiota during pregnancy affected offspring irrespective of vaginal or cesarean birth, and there were no significant differences in the gut microbiota of the adult offspring of germ-free versus conventionally housed mice, suggesting that the effects were not mediated through offspring microbiota. However, there were significant differences in the amounts of circulating acetate, propionate, and butyrate in both the mothers and embryos when comparing germ-free and conventionally housed mice.
Kimura et al. examined expression of the SCFA receptors, G protein–coupled receptor 41 ( Gpr41 ) and Gpr43 , in the brain, intestine, and pancreas of embryos and adult mice. High expression in embryonic tissues suggested that embryos were sensing maternal-derived SCFAs through Gpr41 and Gpr43 . However, they observed lower Gpr41 expression in the germ-free mice. Loss of Gpr41 expression in mice resulted in defects in sympathetic nerve projections to the heart, which were also apparent in germ-free offspring. The ability of the SCFAs to activate sympathetic neuronal differentiation was confirmed in vitro, with propionate having the greatest effect. In mice lacking Gpr43 , the authors found SCFA- and microbiota-dependent defects in embryonic enteroendocrine and pancreatic β-cell development. These data strongly suggest that altered SCFA signaling through GPR41 and GPR43 in embryonic tissues could affect development. Indeed, Kimura et al. showed that the offspring of mice fed a low-fiber diet during pregnancy had increased risk of obesity and insulin resistance. The deleterious effects of a low-fiber diet could be rescued with propionate supplementation. When pregnant mice were given antibiotics, there was no difference in the metabolic parameters of the offspring of high-fiber versus low-fiber diet–fed mothers, confirming the importance of maternal microbiota in mediating protection.
Although several studies have found differences in the gut microbiota of lean or obese humans ( 7 ), the study of Kimura et al. suggests that early exposure to microbial products may be causal in later obesity even if there are no differences in the subsequent gut microbiota of the offspring. The offspring of the high-fiber–fed animals were heavier at birth, but protected against obesity later in life. This is consistent with humans, where low birth weight is associated with future obesity ( 8 ). Supplementation of pregnant mice with propionate protected offspring against future disease. However, whether propionate supplementation had any effects on the mother was not assessed. Propionate supplementation in humans is associated with weight loss and improved metabolic function ( 9 ), although studies are conflicting, with propionate also reported to increase insulin resistance ( 10 ).
Given the goal of reducing human metabolic disease, it is crucial to determine whether similar mechanisms control human development. There is an urgent need to better understand how, why, and under what circumstances should attempts be made to modulate gut microbiota or SCFAs in pregnancy. Diets high in fiber are consistent with existing nutritional recommendations, including during pregnancy, but whether these would be effective in increasing SCFAs and protecting offspring from future metabolic disease remains unclear. There is large interindividual variability in the microbial composition of humans, with different microbiota having differing capacities for SCFA production ( 11 ). Thus, differences in the SCFA-producing capacity of the microbiota may affect risk of offspring obesity despite high consumption of fiber during pregnancy. Although supplementation with propionate may be a convenient option, the safety and efficacy during pregnancy remain to be determined. Further studies in humans are warranted to understand whether modulation of this pathway could be an avenue to improving the metabolic health of the next generation.
bump.ok im done. I was actually looking for something else, but then started to glance at my old topics.